Hypophosphatasia is a rare, inherited and sometimes fatal metabolic disorder that affects the bones and teeth.
The condition disrupts mineralization, where calcium and phosphorus are deposited in bones and teeth. This process is critical to ensuring that bones are strong and teeth are able to withstand grinding and chewing.
The clinical signs and symptoms of hypophosphatasia are heterogeneous, varying widely between individuals and occurring at any time from before birth through to adulthood. In the most severe cases of the disorder, symptoms tend to develop before birth and during early infancy.
Severe forms of hypophosphatasia are estimated to affect around 1 in 100,000 newborns, while milder forms that develop during childhood or adulthood are thought to occur more frequently. This condition affects people from various ethnic backgrounds, but appears to be more common among white populations. Hypophosphatasia is most common among the Mennonite population in Canada, where it affects approximately 1 in 2,500 infants.
Hypophosphatasia causes the bones to soften and become weak, leading to skeletal abnormalities. In the most severe forms of the condition, children are born with short limbs, soft skull bones and underdeveloped ribs that distort chest shape. Further complications include respiratory problems, poor feeding, failure to gain weight and a raised blood calcium level that can lead to recurrent vomiting and kidney malfunction.
Hypophosphatasia that develops during childhood or adulthood is usually less severe than the forms that develop during infancy. In childhood hypophosphatasia, one of the first features of the disorder is premature loss of baby (primary) teeth. Other features include short stature, abnormally shaped skull bones, enlarged joints and bowed legs. Hypophosphatasia that develops during adulthood is characterized by a condition called osteomalacia, which is a softening of the bones that can lead to recurrent and painful foot and thigh fractures. Adults may also lose their teeth prematurely and are at risk of developing pain and inflammation in their joints.
The mildest form of hypophosphatasia affects only the teeth, a condition referred to as odontohypophosphatasia. Here, the teeth develop abnormally and tooth loss occurs prematurely, but the skeletal abnormalities seen in other forms of the disease are absent.
Hypophosphatasia is caused by mutations in a gene called ALPL, which codes for an enzyme called alkaline phosphatase (ALP). ALP plays a vital role in the mineralization of bones and teeth. ALPL mutation leads to the production of an abnormal version of this enzyme that cannot contribute properly to the mineralization process, meaning bones become soft and weak. Calcium and phosphate build up in other parts of the body, which damages structures such as the brain, lungs, muscles, kidneys and joints.
The mutations in ALPL that almost completely eliminate ALP activity are responsible for the more severe forms of hypophosphatasia, while milder forms are caused by mutations that reduce rather than eliminate ALP activity.
The severe forms of hypophosphatasia that develop during early life are inherited in an autosomal recessive manner, meaning both copies of the ALPL gene in each cell are mutated. Milder forms that develop during childhood may have an autosomal recessive or autosomal dominant inheritance pattern. In the case of autosomal dominant inheritance, only one copy of the ALPL gene in each cell needs to be mutated for the condition to develop. Adult hypophosphatasia and odontohypophosphatasia are usually inherited in an autosomal dominant manner, but may be autosomal recessive in rare cases.
People with hypophosphatasia are affected by the condition on a day-to-day basis. Children who develop the condition may be slow to crawl, stand and walk and may not be able to perform basic activities as easily or as early on as other children. Adults who have the condition also experience mobility problems and for them, walking, running, climbing stairs, carrying objects and even standing can be problematic.
Hypophosphatasia is diagnosed based on the presence of signs and symptoms characteristic of the condition, a thorough assessment of medical history and various laboratory tests including a blood test to check the serum ALP activity and an X-ray to identify bone abnormalities.
There are no medications that can treat hypophosphatasia and therapy is aimed at managing the symptoms and complications of the condition to help affected individuals remain active and maintain a good quality of life. Treatment may be a coordinated effort made by specialists from various fields including dentistry, pediatrics, orthopedics and pain management, for example.
Non-steroidal anti-inflammatory drugs (NSAIDs) may be administered to ease pain in the joints and bones and vitamin B6 can help to control seizure in babies. Severely affected infants who develop hypercalcemia may also have their dietary calcium intake restricted and receive hydration therapy, diuretics and sometimes calcitonin. Regular dental care should be initiated early on in life and physical and occupational therapy may be advised in some cases.
Adults who frequently suffer from bone fractures may be treated using a process called orthopedic internal fixation or “rodding,” where a metal rod is placed though the opening of a bone to strengthen and stabilize it. Special devices designed to help manage foot fractures may also be used.